Salmonella enterica serotype Typhi causes a severe systemic infection in humans, termed typhoid fever, which is responsible for an estimated 600,000 deaths annually. The pathogenesis of typhoid fever is only poorly understood due to the lack of suitable animal models. S. enterica serotype Typhimurium infection of mice is commonly used as a model to study the pathogenesis of S. Typhi infections in humans. A limitation of this approach is that S. Typhimurium does not cause typhoid fever in humans, but rather causes a localized gastroenteritis resulting in diarrhea. The observation that humans infected with S. Typhi or S. Typhimurium develop different disease syndromes (i.e. typhoid fever vs. gastroenteritis) illustrates that some virulence mechanisms important for the pathogenesis of typhoid fever are only present in S. Typhi. The rationale for the proposed research is that a complete understanding of the pathogenesis of typhoid fever will require studies that focus on eliciting S. Typhi-specific virulence mechanisms. Our long-range goal is to elucidate the molecular mechanisms by which Salmonella serotypes manipulate host responses during infection. The objectives of this application are to study the mechanism by which the viaB locus, a S. Typhi- specific DNA region, contributes to host pathogen interaction. Our central hypothesis is that TviA, a regulatory protein encoded by the viaB locus, coordinates changes in bacterial gene expression that enable S. Typhi to evade innate immunity, thereby contributing to the development of host responses that distinguish typhoid fever from gastroenteritis. We will test different aspects of our hypothesis and accomplish the objectives of this application by pursuing the following two specific aims: 1. Investigate the mechanisms by which TviA manipulates the interaction of S. Typhi with the innate immune system. 2. Determine the role of the viaB locus in generating disease manifestations that distinguish typhoid fever from infections with non-typhoidal Salmonella serotypes. The proposed studies will take an innovative approach that links clinical observations to molecular virulence mechanisms. By establishing these connections, our studies are expected to demonstrate that TviA- mediated innate immune evasion is a S. Typhi-specific virulence mechanism that can explain several disease manifestations that distinguish typhoid fever from gastroenteritis. This outcome is significant because it will establish a new paradigm in Salmonella pathogenesis, which is expected to have a measurable impact on the field of bacterial pathogenesis. PUBLIC HEALTH RELEVANCE: Typhoid fever is a major human disease syndrome caused by the strictly human adapted Salmonella enterica serotype Typhi. Due to the absence of convenient animals models to study S. Typhi, our understanding of typhoid fever pathogenesis is still incomplete. In this application, we will characterize a S. Typhi-specific virulence factor, the viaB locus, which will provide important new insights into the pathogenesis of typhoid fever.